Testosterone 4, 4-dimethyl pentanoate



Patented Apr. 22, 1958 United States Patent ce 2,831,873

and the compound 4,5-dihydrotestosterone, which has the formula 2,831,873

TESTOSTERONE 4,4-DIMETHY L PENTANOATE OH Ellis Rex Pinson, Jr., and Gerald D. Laubach, Jackson Heights, N. Y., assiguors to Chas. Pfizer & (30., Inc., Brooklyn, N. Y., a corporation of Delawur No Drawing. Application October 13, 1954 Serial No. 462,104

iclaim. (cl.260-397.4

. r are androgens. Like testosterone, they each have a hy- Thzs invention is concerned with certain novel comdroxyl group at the IDS-position and may readily be used pounds useful because of their high androgenic activity to prepare these novel esters. and because of the long duration of tal'i'atactivity. It is For convenience, throughout this paragraph the term also concerned with the preparation of these new comuseful'acid is used to mean an acid which meets the pounds. requirements of the formula given above for the acids it has long been known to the art that certain esters used in this invention. No unusual or particular process of androgenic alcohols such as testosterone exhibit activneed be employed to make an ester of an androgenic ity of longer duration than do the free alcohols from alcohol and a useful acid. Any of the well known, which they are prepared (see U. S. Patent 2,109,400) It standardized: procedures Works. The steroid androgenic has now been discovered that a particular kind of ester, alcohol may be aeylated with such acylating agents as heretofore unknown, has great advantages over previously the useful acid itself, the a-eyl halide of a useful acid, known ones. These new esters combine high androgenic the acid. anhydrideof auseful acid and the lower molecactivity with unprecented duration of that activity. They ular. weight alkyl. esters, e. g. the methyl ester, of a usealso have the advantage of physical properties making ful acid. Transesterifi'cati'on also works; In this process them suitable for being injected into patients both in a lowimolecular weight ester, e. g. theacetate, of anandrothe form of an oil solution and of an aqueous crystal 3O genie alcohol; is reacted with an ester of :a useful acid suspension. and of a low molecular Weight alcohol, e. g; methanol. These new esters are characterized by being derived Areaction' analogous todou'ble decomposition takes place, from acids having the fonnula resulting in the formation of an ester of an androgenic CH3 (CH2)m C(CH3)2 (CH2)n+COOH alcohol and of a useful acid, with the formation. of a low A I boiling by-product, methyl acetate for example, which is Whfirein m is a number from F P elght mcl'u'slve, removed by gentle heating under reduced pressure to is a number from two to ten inclusive, and the sum of force1 the madden to completion Although in transm and n is P fourteen esterification an ester rather than the androgenic alcohol This inventlon 15 the morve Summing m itself is the starting material, it is to be understood that the fact a fisters androgen? alcohols of acids this process, as well as the other esterificatilo'n' processes, in which n m the f f l 1S f One is included in the expression esteri'fying a steroid an- Pletely inactive when Injected mm l hydrogen selected from the group consisting of testo- Testosterone and a number of Q P sterone, l9-nortestosterone and 4,5-dihydrotestosterone ly related to it possess great androgenlc activity. The with a reagent which contains the Structure formula for testosterone 1s 5 O 511 C T'(CHB)M' C(G S)! (CH1)7L wherein m is a number from Zero to eight inclusive, n is a number from two to ten inclusive, and the sum of m and n is less than. fourteen.

It. is well: known that the esterificat-ionprocess may be catalyzed by such materials as ion-exchange resins, and minor proportions. of strong acids or alkalies, either 02 organic or inorganic. Naturally the selection of the cata- 5 lyst must be such that the catalyst does not cause undesirable side reactions; The use of catalytic amounts The compound 19 nortestosterone, which has the formula of a base or acid for spewing the esterification process is, of course, not necessary when an acylating agent such H R as an acid anhydride or acid halide is used. The agents 60 of this latter group may be utilized in the presence of an organic base such as pyridine, dimethylaniline, quinoline, etc.

In operating the process, it is advisable to use a solvent, if an organic base such as pyridine is not used for this purpose. Inert organic solvents, such as benzene, chloro 0: form, toluene, etc. may be used. The application of heat often assists in speeding the reaction to its completion, but caution should be observed when an acyl halide is being employed. Optimum conditions for the reaction will, of course, vary somewhat with the particular androgen and acetylating agent employed, but the ester products of the present invention may be obtained in crystalline form and in good yield without great difiiculty.

Each of the esters of this present invention, i. e. esters of an androgenic alcohol selected from the group consisting of testosterone, l9-nortestosterone and 4,5-dihydro* testosterone, and of an acid having the formula wherein m is a number from zero to eight inclusive, n is a number from two to ten inclusive, and the sum of m and n is less than fourteen, is extremely useful. The esters are all high melting and exist as hard crystals. For this reason they, unlike previously reported compounds, may be injected into patients in the form of aqueous crystal suspension. The crystals so used maybe obtained either upon direct crystallization or by milling the crystals (possible because of their hardness) to the desired size. These compounds have the added advantage of also being suitable for injection into patients in oil solution, for example using sesame oil, peanut oil, or other commonly used oil as the solvent. Most significantly, these esters exert powerful androgenic effect of unprecedented duration. The esters in the present invention may be administered in a variety of other pharmaceutica'lly acceptable carriers, that is any medium which is not deleterious to the compounds themselves, nor to the patient. The nature of the vehicle will depend on the chosen route of administration, but the choice of vehicle follows accepted pharmaceutical practices.

This long duration of androgenic activity is illustrated by the following chart. Castrated rats were each given a single injection of a sesame oil solution of a testosterone ester containing the equivalent (calculated from molecular weights) of five milligrams of testosterone. Control rats were given an injection of plain sesame oil. At the end of two, four and six weeks, rats were sacrificed and the weight of the ventral prostate gland determined.

WEIGHT (mg.) OF VENTRAL PROSTATE AFTER WEEKS control 16. 7 8. 9 6. 7 testosterone propionate 40. 6 10. 4 7. 2 testosterone 4,4-dlmethy1pentanoate. 189. 4 186. 4 119.3

The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the spirit or scope thereof. Example I and was removed by filtration.

M. P. 130.9131.3 C. [a] +98.7 (0.55 CI-ICl A 240 mu.

When applied to 19-nortestosterone and 4,5-dihydrotestosterone, this procedure resulted in the formation of the corresponding ester in each case.

Example II A solution of one part of testosterone in four parts of dry pyridine was refluxed with 1.5 parts of 4,4-dimethylpentanoic acid anhydride for 2 hours. The reaction mixture was then poured into water. The ester crystallized After recrystallization from methanol the product, testosterone 4,4-dimethylpentanoate, was found to be identical with the product of Example I.

When applied to 19-nortestosterone and 4-dihydrotestosterone, this procedure resulted in the formation of the corresponding ester in each case.

Example 111 Testosterone acetate was dissolved in toluene containing 2% hydrogen chloride. An equivalent amount of methyl 4,4-dimethylpentanoate was added, and the mixture was warmed gently at about 40 C. for 4 hours, at the end of which time the pressure was lowered and methyl acetate distilled over. The toluene solvent was also distilled over, and the crystalline residue was recrystallized from ethanol. The crystals obtained were testosterone 4,4-dimethylpentanoate.

In similar fashion ester interchange reactions were used with comparable results to prepare esters of 19-nortestosterone and of 4,5-dihydrotestosterone.

Example IV By the above described methods, esters of other acids and of testosterone, 19-nortestosterone and 4,5-dihydrotestosterone were prepared. These other acids included, for example, 5,5-dimethylhexanoic acid, 4,4-dimethylhexanoic acid, 4,4-dimethylheptanoic acid, 5,5-dimethylheptanoic acid, 6,6-dirnethylheptanoic acid, etc. The syritheses of these acids and of the others having the required formula presented no difficulty, and well known, standardized methods were used.

What is claimed is:

Testosterone 4,4-dimethylpentanoate.

References Cited in the file of this patent UNITED STATES PATENTS 2,109,400 Miescher Feb. 22, 1938 2,143,453 Ruzicka Ian. 10, 1939 2,173,337 Miescher Sept. 19, 1939 FOREIGN PATENTS 208,889 Switzerland May 16, 1940 208,890 Switzerland May 16, 1940 208,899 Switzerland June 1, 1940 

